The Sda and Cad glycan antigens and their glycosyltransferase, β1,4GalNAcT‐II, in xenotransplantation

Abstract

Antibody-mediated rejection is a barrier to the clinical application of xenotransplantation, and xenoantigens play an important role in this process. Early research suggested that N-acetyl-D-galactosamine (GalNAc) could serve as a potential xenoantigen. GalNAc is the immunodominant glycan of the Sda antigen. Recently, knockout of β1,4-N-acetylgalactosaminyltransferase 2 (β1,4GalNAcT-II) from the pig results in a decrease in binding of human serum antibodies to pig cells. It is believed that this is the result of the elimination of the GalNAc on the Sda antigen, which is catalyzed by the enzyme, β1,4GalNAcT-II. However, research into human blood group antigens suggests that only a small percentage (1%-2%) of people express anti-Sda antibodies directed to Sda antigen, and yet a majority appear to have antibodies directed to the products of pig B4GALNT2. Questions can therefore be asked as to (i) whether the comprehensive structure of the Sda antigen in humans, that is, the underlying sugar structure, is identical to the Sda antigen in pigs, (ii) whether the human anti-Sda antibody binds ubiquitously to pig cells, but not to human cells, and (iii) what role the Sda (also called Cad) antigen is playing in this discrepancy. We review what is known about these antigens and discuss the discrepancies that have been noted above.

Carbohydrate antigen expression and anti‐pig antibodies in New World capuchin monkeys: Relevance to studies of xenotransplantation

“…Approximately 90% of humans express and/or secrete the Sd a antigen, with only a small percentage of human subjects (10%) not expressing Sd a antigens on their erythrocytes who may therefore possibly develop anti‐Sd a antibodies. In fact, approximately only 1%‐2% of humans appear to have natural anti‐Sd a antibodies, and these are mainly IgM, not IgG …”

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion

“…In contrast, xenografts from recipients treated with anti-CD4 alone and that went on to experience long-term survival did not show any significant cellular infiltrate or injury on biopsy during the early postoperative period ( Figure 4F, Figure S1 (Figure 6D), a non-αGal antigen produced by the β4Gal-NT2 glycosyltransferase, which has been shown to be a target of anti-pig antibodies in NHPs. 29,30 Because CD4 + T cells were necessary for rejection in our model, we evaluated an alternate strategy to avoid nonspecific CD4 depletion and the potential associated infectious side effects. We generated GGTA1KO pig endothelial cells that either constitutively expressed SLA class I and class II molecules (SLA I + /II + ) or only expressed class I molecules (SLA I + II − Figure 6E).…”

Xenotransplantation literature update, May/June 2019

“…Zhang et al discussed the molecular mechanisms of xenogeneic immunity, coagulation dysregulation and thrombocytopenia . They accurately reaffirm the importance of Gal porcine xenoantigens while also identifying additional non‐Gal xenoantigens aside Neu5Gc, including the Sda/Cad blood group derived from the β4GalNT2 enzyme . The deletion of Gal and non‐Gal antigens in hepatic grafts can have an impact on rejection .…”

“…The deletion of Gal and non‐Gal antigens in hepatic grafts can have an impact on rejection . Zhang et al cite a small selection of the widespread literature surrounding the impact of non‐gal antigens on host graph survival and speak from experince but have not provided data on one GalT‐KO porcine liver failing within one day of transplant and biopsy revealing histopathological hyperacute rejection suggestive of non‐Gal antigen‐mediated hepatic graft injury . It will be interesting to review these assertations further if their study results are formally published.…”